Presenile and senile dementia of the Alzheimer's type is presently one of the most important causes of disability. Histopathologically Alzheimer's disease is characterized by distinct features foremost of which is the presence of senile plaques which contain material meeting all the criteria for amyloid. Indeed, fibrillar deposits which stain with Congo red to give green birefringence by polarization microscopy are usually found in the senile plaques in patients with Alzheimer's disease as well as in the walls of intracerebral blood vessels. Whether there is one or more than one amyloid substance in these locations is not known. Furthermore, it is not known whether the amyloid substance is reactive in nature and/or plays a primary role in the pathogenesis of the dementia. The objective of this proposal is to isolate and characterize the protein or proteins which are contained in the intracerebral amyloid deposits in Alzheimer's disease. The working hypothesis is that the amyloid deposits are composed of a small subunit protein which is deposited in a beta pleated sheet configuration as has been shown for immunoglobulin light chains in primary amyloidosis, protein AA in secondary amyloidosis and prealbumin in hereditary amyloidosis. It is proposed to isolate the amyloid fibrils from central nervous system tissues of patients dying with Alzheimer's disease and use these fibril preparations to isolate the subunit protein or proteins. Light microscopy of Congo red stained materials and electron microscopy will be used to follow the extraction procedure as well as to analyze the amount of amyloid material in individual brains and demonstrate the feasibility of extraction procedures. Chemical analysis of the amyloid fibril preparations will be done by solubilizing the amyloid fibrils in denaturing solvents and fractionation by chromatography both on Sepharose gels and by high performance liquid chromatography. Amino acid analysis of isolated subunit proteins and amino acid sequencing of tryptic peptides of the subunit proteins will be used to characterize the isolated products. The chemical characterization by primary structure of amyloid subunit proteins in Alzheimer's disease will allow the determination of whether the amyloid is a product of 1) normal proteins such as neuroendocrine peptide or prealbumin, 2) a variant form of a normal human protein such as has been described for prealbumin variants in hereditary amyloidosis or 3) the product of an infectious agent such as has been suggested in scrapie.